Antiemetic N-substituted benzamides

ABSTRACT

Compounds of the general formula: ##STR1## wherein the various substituents are defined hereinbelow have pharmacological properties rendering them useful as antiemetic agents with reduced undesirable side-effects. Various methods are described for their preparation involving formation of the amide link, etherification of the 2-hydroxy derivative, introducing the R 5  CH 2  group on the N-unsubstituted azabicyclooctane or nonane or, for 4-amino compounds by hydrolysing a 4-acylamino derivative.

DESCRIPTION

This invention relates to new N-substituted benzamides, methods fortheir preparation, intermediates involved in these methods, compositionscontaining them and their use in medical treatment.

N-substituted benzamides have been shown to possess a number ofpharmacological properties most of which are related to their ability toantagonize the central and peripheral effects of dopamine and/orfacilitate the release of acetylcholine onto muscarinic receptors in thegastrointestinal smooth muscle. This had led to their successfulclinical use as antiemetic and in the treatment of a wide range ofgastrointestinal disorders of somatic, psychosomatic and iatrogenicorigin.

European Pat. Appl. No. 099789 A₁ disclosed a series of new benzamidesof whichN-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxy-4-amino-5-chlorobenzamide(INN, Zacopride) is the most important as potent antiemetic. In contrastto other known antiemetic compounds as Metoclopramide(N-[2-(diethylamino)ethyl]-2-methoxy-4-amino-5-chlorobenzamide, thecompounds of the above mentioned Patent, do not present antidopaminergiceffects which are associated with extrapyramidal symptoms and sideeffects related to hyperprolactinemia. However, the benzamides of theabove mentioned Europ. Pat. Appln. present a spectrum of antiemeticactivity more limited than Metoclopramide as they are not active intests such as CuSO₄ -induced vomiting in the dog.

We have now found that the introduction of new groups in the 2 positionof the benzamide ring, provides new compounds that present not only awide spectrum of antiemetic activity, but also a lack ofantidopaminergic side effects.

Consequently the new N-substituted benzamides of the invention representan important advance in respect to Metoclopramide and related compoundsas those described in the above patent.

Accordingly, the present invention provides a compound of the formula:##STR2## wherein R¹ represents a hydrogen atom or a lower alkyl oracetyl group,

R² represents a halogen atom (preferably chlorine or bromine),

R³ represents a group of formula: ##STR3## in which R⁵ represents ahydrogen atom or a phenyl or a non-aromatic cyclic ether group(preferably tetrahydrofuryl, or 1,3-dioxolanyl), and n represents 2 or3,

R⁴ represents a C₃ -C₆ cycloalkyl, cyclohexenyl (preferably3-cyclohexenyl), lower alkoxy, trifluoromethyl, tetrahydrofuryl,1,3-dioxolanyl or phenoxy group,

m represents an integer from 0 to 4 with the proviso that when m is 0,R⁴ is only a C₃ -C₆ cycloalkyl or tetrahydrofuryl group, andpharmacologically-acceptable acid addition salts thereof.

The qualification "lower" as applied herein to alkyl and alkoxy groupsmeans that the group in question contains at most 6 (and preferably notmore than 4) carbon atoms. In the compounds of the invention of generalformula I, when R⁵ represents a non-aromatic cyclic ether group, itmeans that R⁵ contains no aromatic ring system but contains one ringsystem having from 2 to 6 ring carbon atoms and one or two ring oxygenatoms (e.g. tetrahydrofurane, tetrahydropyrane, 1,3-dioxolane and 1,4dioxane).

Of the N-substituted benzamides of general formula I those wherein R¹represents a hydrogen atom, R² represents a chlorine atom, R³ representsa group of formula II, R⁴ represents a cyclopropyl or lower alkoxy groupand m represents 1 or 2, are of particular importance. Preferredcompounds areN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamideandN-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxyethoxy-4-amino-5-chlorobenzamide.

According to a feature of the present invention, the compounds of theinvention are prepared by the process which comprises reacting areactive derivative of a benzoic acid of the general formula: ##STR4##(wherein the various symbols are as hereinbefore defined) with an amineof the general formula V:

    H.sub.2 N--R.sup.3                                         V

wherein R³ is as hereinbefore defined. The reactive derivative of thesaid benzoic acid may be, for example, a halide (preferably chloride),an alkyl ester (preferably methyl ester), an anhydride or a mixedanhydride. The benzoic acid of general formula IV in which R⁴ representsa C₃ -C₆ cycloalkyl group is novel and represents a further aspect ofthis invention. It is prepared by condensation of a lower alkyl ester ofthe corresponding 2-hydroxy acid with the appropriate halogenderivative, and finally, hydrolysing the carboalkoxy grup to carboxye.g. with alkali.

The reaction of IV with V is preferably carried out in the presence ofan inert organic solvent, for example benzene, toluene, chloroform,tetrahydrofuran, N,N-dimethylformamide or dioxan, at a temperaturebetween -5° and 120° C.

Halides of the benzoic acids of general formula IV can be prepared byreaction of the acid with thionyl chloride or a phosphorus halide in thepresence of an inert organic solvent such as benzene, toluene or ahalogenated hydrocarbon. Mixed anhydrides of the benzoic acids ofgeneral formula IV can be prepared by the reaction of the acid with, forexample, an alkyl chloroformate in the presence of an organicnitrogen-containing base, e.g. triethylamine, in an inert organicsolvent, e.g. tetrahydrofuran, N,N-dimethylformamide or methylenechloride and at a temperature between -20° and +25° C. Esters andanhydrides of the benzoic acids of formula IV, which may be employed asstarting materials in the aforementioned process, can be prepared fromthe benzoic acids by methods known per se.

In the preparation of those compounds of general formula I wherein thesymbol R¹ is hydrogen it is sometimes advisable to use as startingmaterial corresponding compounds in which the amino group is protectedby an acyl group, the acyl protecting group preferably being acetyl,chloroacetyl, trifluoracetyl or phthaloyl. After the reaction theN-acylated intermediate products are subjected to alkaline hydrolysis togive the corresponding compounds of general formula I in which R¹represents a hydrogen atom. When R⁵ is other than a non aromatic cyclicether group, and R⁴ is a C₃ -C₆ cycloalkyl, cyclohexenyl or a loweralkoxy group, the N-acylated intermediate products can also be subjectedto acid hydrolysis. Alkaline hydrolysis of the N-acylated compound ispreferably carried out at a temperature between 20° and 90° C. withsodium or potassium hydroxide in an aqueous-alcoholic solution, whileacid hydrolysis is preferably carried out by heating with dilutehydrochloric acid at the boiling point of the reaction mixture.

The compounds of the invention, in which R³ is a group of formula III asdefined above, can also be prepared from an N-unsubstituted compound offormula: ##STR5## wherein the various symbols are as hereinbeforedefined. The compound VI which is novel and represents a further aspectof this invention, is prepared by subjecting the corresponding N-benzylcompound to catalytic hydrogenolysis in a solvent such as a C₁ -C₆alcohol in the presence of a noble metal catalyst, e.g. palladium orplatinum, which may be absorbed on an inert support such as carbon orbarium sulphate, in the presence of hydrogen at normal or elevatedpressure and at temperatures between room temperature and 100° C. Thecompound VI in which R¹ is other than acetyl group can also be preparedby hydrolysing the corresponding lower alkoxy carbonyl ester, preferablyan ethoxycarbonyl compound of formula VII: ##STR6## (wherein R1' is ahydrogen atom or a lower alkyl group and the other symbols are ashereinbefore defined) with alkali e.g. sodium or potassium hydroxide inan organic solvent, for example ethanol or isopropanol, at the boilingpoint of the solvent. The compound VI may then be reacted with anappropriate halide or sulphonate of structure:

    W--CH.sub.2 --R.sup.5                                      VIII

where W is a halogen atom or a sulphonate such as a methanesulphonate,p-toluenesulphonate or benzenesulphonate group and R⁵ is as definedabove, in the presence of a base such as sodium or potassium carbonateor sodium or potassium bicarbonate, in an organic solvent such astoluene, dioxane or methyl isobutyl ketone at a temperature between 40°and 140° C.

The compounds of general formula I can also be prepared, according to afurther feature of the invention, by the direct reaction of a benzoicacid of general formula IV with an amine of general formula V,preferably in the presence of an appropriate dehydrating agent. Suchagents include silicon tetrachloride, a mono-, di or trialkylsilylchloride, titanium tetrachloride, N,N'-dicyclohexyl-carbodiimide,carbonyl diimidazole, thionyl chloride, sulphur trioxide in dimethylsulphoxide, toluene-p-sulphonyl chloride, acetone dimethyl acetal or apolymeric dehydrating agent. The reaction can be carried out in an inertorganic solvent, e.g. methylene chloride, acetone, pyridine, ethylacetate or dioxan, at a temperature between 20° and 110° C. Thecompounds of the invention of formula I can also be prepared from thehydroxy derivative of formula IX: ##STR7## wherein the various symbolsare as hereinbefore defined, by reaction with a halogen derivative offormula X:

    Z--(CH.sub.2).sub.m --R.sup.4                              X

wherein Z is chloro, bromo or iodo and R⁴ and m are as hereinbeforedefined. The reaction is preferably carried out in an organic solventsuch as methyl isobutyl ketone, N,N-dimethylformamide, dioxane, ortoluene at a temperature between 40° and 140° C. and in the presence ofan organic or inorganic base such as sodium or potassium carbonate.

The intermediate amines of formula V wherein R³ is III can give alphaand beta isomers according to whether the amino group is in the axial orequatorial position. Both isomers an be prepared by the methodsdisclosed in Eur. J. Med. Chem. 1984, 19, p. 105-110 and J. HeterocyclicChem. 19, 485 (1982).

The benzoic acids starting materials IV, in which R⁴ is other than C₃-C₆ cycloalkyl, used in the preparation of the compounds of theinvention, are prepared according to the general methods described, forexample, in GB No. 1,507,462, GB No. 1,088,581 and GB No. 1,019,781.

The N-substituted benzamides of general formula I can be converted bymethods known per se into acid addition salts, for example by reactionof the basic compounds with acids in appropriate solvents, for examplealcohols, dialkyl ketones or ethers. Suitable acid addition salts arethose derived from inorganic acids, for example the hydrochlorides andsulphates, and organic acids, for example, the fumarates, acetates,succinates and citrates. Also included within the scope of the inventionare N-oxides and pharmaceutically acceptable quaternary ammonium saltsof N-substituted benzamides of general formula I in which the cyclicnitrogen atom is quaternised by reaction for example with a C₁ -C₆ alkylhalide or sulphate.

The N-substituted benzamides of general formula I have potentgastrokinetic and antiemetic activities and block 5-HT₃ receptors in theabsence of dopamine antagonist effects.

The pharmacological screening of compounds to optimise these effects wascarried out using the following tests:

(1) Stimulation by 5-HT of 5-HT₃ receptors located in vagal afferentfibres produces a fall in heart rate and blood pressure in theanaesthetized rat (Bezold-Jarisch reflex). (Fozard, J. R. & Host, M. Br.J. Pharmacol. (1982) 77: 520P)

(2) Cis-platinum induced emesis in the dog administering compounds byoral or intravenous route. (Gylys, J. A., Doran, K. M. & Buyniski J. P.Res. Comm. Chem. Pathol. Pharmacol. (1979) 23: 61-68).

(3) Cu SO₄ -induced emesis in the dog administering compounds bysubcutaneous or intravenous route. (Kayashima, N., Tanaka, M., Iwasaki,M. & Hayama, T. Japan J. Pharmacol. (1978) 28: 775-781).

(4) Apomorphine-induced emesis in the dog administering compounds bysubcutaneous or intravenous route. (Prala, J. J., High, J. P., Hasses,G. L., Burke, J. C. and Craven, B. N. J. Pharmac. Exp. Therap. 127,55-65, 1959).

(5) Stomach emptying in the rat, administering compounds by oral route.(Jacoby, H. I., and Brodie, D. A. Gastroenterol. 52, 676-684, 1967).

The N-substituted benzamides of general formula I were compared withMetoclopramide(N-[2-(diethylamino)ethyl]-2-methoxy-4-amino-5-chlorobenzamide) andZacopride(N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxy-4-amino-5-chloro-benzamide)and were shown to have advantageous antiemetic profiles due to thepresence of the new substituents in position 2 of the benzamide group.

As shown Table I, compounds of general formula I, produce a potentinhibition of the Bezold-Jarisch reflex in the rat at a dosage level100-800 times lower than Metoclopramide. This activity has been recentlyrelated to the ability of antagonising the cytotoxic drug-inducedvomiting. In fact, all of them inhibit the cisplatin-induced vomiting inthe dog and particularly compound 1 shows a similar potency toZacopride.

Metoclopramide decreases the number of emetic episodes in the CuSO₄-induced vomiting in the dog, the new compounds have significantactivity in this test, whereas Zacopride is totally inactive.

Like Zacopride, the new compounds lack antiemetic activity in theapomorphine-induced vomiting in the dog whereas Metoclopramide is a veryactive compound in this test. All of them show a good prokineticactivity in the gastric emptying of glass beads in the rat.

In conclusion, the present results clearly indicate that N-substitutedbenzamides of general formula I have a broader antiemetic spectrum thanZacopride without the dopamine antagonistic activity of Metoclopramide,and therefore without the potential for associated extrapyramidal sideeffects.

    TABLE I        C.sub.4 SO.sub.4 -INDUCED APOMORPHINE-   CISPLATIN-INDUCED VOMITING     VOMITING IN INDUCED GASTRIC EMPTYING BEZOLD-JARISCH IN THE DOG THE DOG     VOMITING IN IN THE RAT       REFLEX IN THERAT N°EMETIC EPISODES     (% inhibition) 1 mg/kg i.v.N° EMETIC EPISODES THE DOG1 mg/kg i.v.      ##STR8##      COMPOUND (ID.sub.50 ; μg/kg i.v.) 0.03 mg/kg i.v. 0.1 mg/kg p.o. (%     Inh.) % Protected animals 0.01 mg/kg p.o. 1.0 mg/kg p.o.       METOCLOPRA  69 85     MIDE 330 (1 mg/kg i.v.) (3 mg/kg p.o.) 60 100 0     42 ZACOPRIDE 0.21 92 88 0 0 51 77 Compound 11 0.42 81 0 24 0 60 68     Compound 1 0.56 88 85 40 0 55 85 Compound 23 0.63 31 53 30 0 13 61     Compound 16 2.6 53 61 45 0 32 71     Compound 11: N--(1azabicyclo[2.2.2]oct     3yl)-2-methoxyethoxy-4-amino-5-chlorobenzamide     Compound 1: N--(1azabicyclo[2.2.2]oct     3yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide     Compound 23: N--(8methyl-8-azabicyclo[3.2.1]oct     3β-yl)2-methoxyethoxy-4-amino-5-chlorobenzamide     Compound 16: N--(8methyl-8-azabicyclo[3.2.1]oct     3β-yl)2-cyclopropylmethoxy-4-amino-5-chlorobenzamide

The N-substituted benzamides of general formula I also presentanalgesic, anxiolytic and antimigraine activity as a consequence oftheir anti 5-HT₃ activity.

The present invention also provides pharmaceutical compositions whichcomprise, as active ingredient, at least one compound of general formulaI, or a pharmacologically acceptable salt in association with apharmaceutically acceptable carrier or diluent. The active ingredientmay comprise 0.0001% to 99% by weight, preferably 0.001% to 90% byweight of the composition depending upon the nature of the formulationand whether further dilution is to be made prior to application.Preferably the compositions are made up in a form suitable for oral,topical, percutaneous or parenteral administration.

The pharmaceutically acceptable carriers or diluents which are admixedwith the active compound, or compounds or salts of such compounds, toform the compositions of this invention are well known per se and theactual excipients used depend inter alia on the intended method ofadministering the compositions. Compositions of this invention arepreferably adapted for administration per os. In this case, thecomposition for oral administration may take the form of tablets,capsules, lozenges or effervescent granules or liquid preparations, suchas mixtures, elixirs, syrups or suspensions, all containing one or morecompounds of the invention; such preparations may be made by methodswell known in the art.

The diluents which may be used in the preparation of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or capsules may conveniently contain between 0.1 and 20mg of active ingredient or the equivalent amount of an acid additionsalt thereof.

The liquid compositions adapted for oral use may be in the form ofsolutions or suspensions. The solutions may be aqueous solutions of asoluble salt or other derivative of the active compound in associationwith, for example, sucrose to form a syrup. The suspensions may comprisean insoluble active compound of the invention or a pharmaceuticallyacceptable salt thereof in association with water, together with asuspending agent or flavouring agent.

Compositions for parenteral injection may be prepared from solublesalts, which may or may not be freeze-dried and which may be dissolvedin water or an appropriate parenteral injection fluid.

A further aspect of the present invention provides a method of treatingvarious gastro-intestinal disorders including vomiting in mammalsincluding man by administering an effective amount of a compound or saltof formula I, suitably using compositions and administration routesdescribed above. Effective doses are normally in the range of 0.1-100 mgof active ingredient per day.

In another aspect of the invention, the compounds may be mixed withactive anti-acid and anti-ulcer agents (excluding anti-cholinergicagents) for oral or, in appropriate cases, for parenteral use.

The following Examples illustrate the preparation of compounds of thepresent invention.

EXAMPLE 1

To a solution of 2-cyclopropylmethoxy-4-amino-5-chlorobenzoic acid (3.2g; 0.0134 moles) in pyridine (15 ml), a solution of 3-aminoquinuclidinedihydrochloride (2.5 g; 0.0125 moles) and sodium hydroxide (0.5 g;0.0125 moles) in water (15 ml) was added. To the resulting solutionN,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added and themixture stirred at room temperature for 20 hours. An additional amountof N,N'-dicyclohexyl-carbodiimide (3.1 g; 0.0146 moles) was added andthe mixture stirred for a further 24 hours. The insoluble solid wasfiltered off, washed with water and the solvent removed in vacuo at atemperature between 30° and 45° C. The solid residue was taken up inwater, made alkaline with sodium hydroxide and a solid precipitatedwhich was filtered off and dried to giveN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide(4.1 g) M.p 183°-185° C. after recrystallisation from acetonitrile.

EXAMPLE 2

Triethylamine (1.6 ml; 0.0113 moles) and ethyl chloroformate (1.15 ml;0.0113 moles) were added succesively to a stirred solution of2-methoxyethoxy-4-amino-5-chlorobenzoic acid (2.8 g; 0.0113 moles) inmethylene chloride (125 ml) whilst maintaining the temperature between-5° and -10° C. After stirring at this temperature for 2 hours, asolution of 3β-amino-8-methyl-8-azabicyclo[3.2.1]octane (1.6 g; 0.0113moles) in methylene chloride (10 ml) was added, the temperature wasmaintained at -5° to -10° C. for 1 hour and then allowed to reach roomtemperature overnight. The reaction mixture was washed with water,aqueous sodium hydroxide solution, and then with water. After drying(Na₂ SO₄) the solvent was removed in vacuo to give an oil which wasdisolved in ethanol and reacted with the stoichiometric amount offumaric acid. The boiling solution was diluted with isopropanol and oncooling N-(8-methyl-8-azabicyclo[3.2.1]oct-3β-yl)-2-(2-methoxyethoxy)-4-amino-5-chlorobenzamideacid fumarate (1.1 g) crystallized, m.p. 211°-213° C. (d).

EXAMPLE 3

A mixture ofN-(8-azabicyclo[3.2.1]oct-3β-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide(2.3 g; 0.007 moles), 2-bromomethyl-1,3-dioxolane (1.3 g; 0.0077 moles),potassium carbonate (1 g; 0.007 moles) and acetonitrile (100 ml) wasboiled under reflux for 48 hours after which, an additional amount of2-bromomethyl-1,3-dioxolane (0,5 g; 0.003 moles) was added. The reactionmixture was boiled under reflux for other 48 hours and then, the solventwas removed in vacuo, the residue treated with water and extracted withmethylene chloride.

The organic solution was dried (Na₂ SO₄), decolorized with charcoal andthe solvent removed in vacuo to give crudeN-[8-[2-(1,3-dioxolanyl)methyl]-8-azabicyclo[3.2.1]oct-3β-yl-]2-cyclopropylmethoxy-4-amino-5-chlorobenzamide(2.2 g). This compound was purified by column chromatography with silicagel and methanol:ammonium hydroxide (100:1.5) as solvent, m.p. 125°-127°C.

EXAMPLE 4

A suspension ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-hydroxy-4-acetamido-5-chlorobenzamide(6.75 g; 0.02 moles) (m.p. of hydrochloride 315°-317° C. (d)), potassiumcarbonate (2.76 g; 0.02 moles), 91.5% bromomethylcyclopropane (3.54 g;0.024 moles) and methyl isobutyl ketone (40 ml) was boiled under refluxfor 48 hours. After cooling, the reaction mixture was washed with water,1N sodium hydroxide aqueous solution and again with water. The organicsolution was dried (Na₂ SO₄), decolorized with charcoal and the solventremoved in vacuo to give crudeN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide(6.6 g) as an oil, which was crystallized from acetonitrile, m.p.211°-213° C. (d).

EXAMPLE 5

A solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide(3.9 g; 0.01 mol), sodium hydroxide (2 g; 0.05 moles), ethanol (50 ml)and water (20 ml), was boiled under reflux for 2 hours. Then the ethanolwas removed in vacuo, the residue diluted with water, and the insolublesolid filtered off and washed thoroughly with water. The obtainedN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide(3.2 g) was purified by recrystallization from acetonitrile, m.p.183°-185° C.

EXAMPLE 6

To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide(3.5 g; 0.01 mol) in acetone (200 ml), iodomethane (2.8 g; 0.02 moles)was added and the resulting mixture stirred to room temperature for 20hours. The precipitated solid was collected, washed with acetone anddried to giveN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chlorobenzamidemethyl iodide (3.9 g), m.p. 274°-276° C. (d) (after recrystallisationfrom a mixture of acetonitrile and water).

EXAMPLE 7

To a solution ofN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamide(2.6 g; 0.007 moles) in acetic acid (20 ml), 30% hydrogen peroxide (1.8ml) was added and the resulting solution was stirred at 80° C. for 15hours. The solvent was removed in vacuo, the residue was treated withwater, alcalinized with sodium hydroxyde aqueous solution, saturatedwith sodium chloride and extracted with methylene chloride. The organicsolution was dried (Na₂ SO₄), the solvent removed in vacuo and theresidual yellow solid treated with diethyl ether and collected. Afterwashing with acetonitrile and diethyl ether,N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-acetamido-5-chlorobenzamideN-oxide was obtained as a white solid, which was dried at 50° C. to give1.4 g; m.p. 234°-236° C. (d).

The compounds of general formula I included in the following Tables IIand III were prepared according to the processes disclosed in Examples 1to 5 as indicated.

                                      TABLE II                                    __________________________________________________________________________     ##STR9##                                                                                           Method                                                                             Base/Salt                                          No                                                                              R.sup.1                                                                             R.sup.2                                                                         R.sup.4   m Example                                                                            form  m.p. °C.                              __________________________________________________________________________    1 H     Cl                                                                               ##STR10##                                                                              1 1,5  Base  183-185                                      2 CH.sub.3                                                                            " "         " 1    ClHH.sub.2 O                                                                        254-256(d)                                   3 COCH.sub.3                                                                          " "         " 1,4  Base  211-213(d)                                   4 H     "                                                                                ##STR11##                                                                              " 1    "     165-167                                      5 "     " "         2 1    ClH   283-285(d)                                   6 "     "                                                                                ##STR12##                                                                              0 1    ClH.1/2H.sub.2 O                                                                    160-197                                      7 "     "                                                                                ##STR13##                                                                              " 1    Base  189-191                                      8 "     " "         1 1    "     167-169                                      9 "     "                                                                                ##STR14##                                                                              " 1    ClH.1/2H.sub.2 O                                                                    197-201                                      10                                                                              "     " "         2 1    ClH   259-61(d)                                    11                                                                              "     " OCH.sub.3 " 1    Base  166-168                                      12                                                                              "     "                                                                                ##STR15##                                                                              " 1    ClH.1/2H.sub.2 O                                                                    232-234                                      13                                                                              "     " CF.sub.3  1 1    ClH.H.sub.2 O                                                                       290-292(d)                                   14                                                                              "     "                                                                                ##STR16##                                                                              " 1    Base  173-175                                      15                                                                              "     "                                                                                ##STR17##                                                                              " 1    "     88-120                                       __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     ##STR18##                                                                                           Method                                                                             Base/Salt                                         No                                                                              R.sup.1                                                                         R.sup.2                                                                         R.sup.4                                                                             R.sup.5                                                                              m n Example                                                                            form      m.p. °C.                         __________________________________________________________________________    16                                                                              H Cl                                                                               ##STR19##                                                                          H      1 2 1,2  Base; β-isomer                                                                     195-197                                 17                                                                              " " "     C.sub.6 H.sub.5                                                                      " " 1,2  "         174-176                                 18                                                                              " " "                                                                                    ##STR20##                                                                           " " 1,3  "         125-127                                 19                                                                              " " "     H      " 3 1,2  "         198-203                                 20                                                                              " " "                                                                                    ##STR21##                                                                           " 2 1,3  C.sub.4 H.sub.4 O.sub.4 (*)                                                             189-191isomer                           21                                                                              " "                                                                                ##STR22##                                                                          C.sub.6 H.sub.5                                                                      0 " 1,2  Base β-isomer                                                                      191-193                                 22                                                                              " " OCH.sub.3                                                                           "      2 " 1,2  "         196-198                                 23                                                                              " " "     H      " " 1,2  C.sub.4 H.sub.4 O.sub.4 β-isomer                                                   211-213                                 24                                                                              " " "     "      " 3 1,2  "         171-173(d)                              __________________________________________________________________________     (*)Fumaric acid                                                          

The following Examples illustrate pharmaceutical compositions accordingto the present invention and procedures for their preparation

EXAMPLE 8

50,000 Tablets each containing 1 mg ofN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide were prepared from the followingformulation:

    ______________________________________                                        N--(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-                                                   50 g                                             amino-5-chlorobenzamide                                                       microcrystalline cellulose   950 g                                            lactose spray dried          4950 g                                           carboxymethyl starch         200 g                                            sodium stearyl fumarate      50 g                                             colloidal silicon dioxide    50 g                                             ______________________________________                                    

Procedure

All the powders were passed through a screen with aperture of 0.6 mm,then mixed in a suitable mixer for 20 minutes and compressed into 125 mgtablets using 6 mm circular and flat bevelled punches. Thedisintegration time of the tablets was about 60 seconds.

EXAMPLE 9

2,000 Bottles (125 ml volume) each containing a solution of 25 mg ofN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamidewere prepared as follows:

    ______________________________________                                        N--(1-azabicyclo[2.2.2]oct-3-yl-2-                                                                      50      g                                           cyclopropylmethoxy-4-amino-5-chlorobenzamide                                  sorbitol                  120000  g                                           sorbic acid               250     g                                           citric acid               250     g                                           distilled water q.s.      250     liters                                      flavouring agent                  q.s.                                        ______________________________________                                    

Procedure

TheN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamideand the sorbic acid were dissolved in 150 liters of water and then thesorbitol, citric acid and flavouring agent were added with stirringuntil dissolution. The mixture was diluted to 250 liters into 125 mlbottles using an appropriate filling machine.

EXAMPLE 10

10,000 Ampoules each containing 0.5 mg ofN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamidewere prepared from the following formulation:

    ______________________________________                                        N--(1-azabicyclo[2.2.2]oct-3-yl-2-                                                                     5 g                                                  cyclopropylmethoxy-4-amino-5-chlorobenzamide                                  sodium chloride          250 g                                                lactic acid              7 g                                                  1N Sodium hydroxide aqueous solution                                                                   q.s. to pH = 3                                       Water injectable grade q.s.                                                                            50 liters                                            ______________________________________                                    

Procedure

TheN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide,the lactic acid and the sodium chloride were dissolved in 40 liters ofwater. The resulting solution was neutralised to pH=3 with the sodiumhydroxide solution, diluted to 50 liters, then passed through abacteria-retaining filter and filled under sterile conditions into 5 mlglass ampoules in known manner.

EXAMPLE 11

5,000 Suppositories each containing 1 mg ofN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamide,were prepared as follows:

    ______________________________________                                        N--(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-                                                    5 g                                              amino-5-chlorobenzamide                                                       theobroma oil                9995 g                                           ______________________________________                                    

Procedure

The theobroma oil was melted and the active compound suspended in it.The mixture was then poured into appropriate suppository moulds to make2.0 g suppositories.

EXAMPLE 12

100,000 Capsules each containing 1 mg ofN-(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-amino-5-chlorobenzamidewere prepared as follows:

    ______________________________________                                        N--(1-azabicyclo[2.2.2]oct-3-yl-2-cyclopropylmethoxy-4-                                                    100 g                                            amino-5-chlorobenzamide                                                       lactose                      10500 g                                          corn starch                  9000 g                                           colloidal silicon dioxide    200 g                                            magnesium stearate           200 g                                            ______________________________________                                    

Procedure

All the powders, previously passed through a screen with an opening of0.6 mm, were mixed for 20 minutes and distributed into 100,000 capsulesof appropriate size using a filling machine.

We claim:
 1. A compound of the formula: ##STR23## wherein R¹ representshydrogen, a C₁₋₆ alkyl group or an acetyl group;R² represents halogen;R³ represents a group of the formula: ##STR24## wherein R⁵ representshydrogen or a phenyl or non-aromatic cyclic ether group and n is 2 or 3;R⁴ represents a C₃₋₆ cycloalkyl, cyclohexenyl, C₁₋₆ alkoxy,trifluoromethyl, tetrahydrofuryl, 1,3-dioxolanyl or phenoxy group; m is0, 1, 2, 3 or 4 with the provisos that when m is 0, then R⁴ is only aC₃₋₆ cycloalkyl or tetrahydrofuryl group, and when R³ is II and m is 1,then R⁴ is only a C₃₋₆ cycloalkyl, cyclohexenyl, C₁₋₆ alkoxy,trifluoromethyl, 3-tetrahydrofuryl or phenoxy group and when R³ is IIand m is 2, then R⁴ is only a C₃₋₆ cycloalkyl, cyclohexenyl,trifluoromethyl, tetrahydrofuryl, 1,3-dioxolanyl or phenoxy group, andwhen R³ is II and m is 3, then R⁴ is only a C₃₋₆ cycloalkyl,cyclohexenyl, trifluoromethyl, tetrahydrofuryl, 1,3-dioxolanyl or aphenoxy group; or a pharmacologically acceptable acid addition salt,quaternary ammonium salt or a N-oxide thereof.
 2. A compound accordingto claim 1 wherein R¹ represents hydrogen or a C₁₋₆ alkyl group, R⁴represents a C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, trifluoromethyl,tetrahydrofuryl, 1,3-dioxolanyl or a phenoxy group and R², R³ and m areas defined in claim
 1. 3. A compound according to claim 1 wherein R¹ ishydrogen.
 4. A compound according to claim 1 wherein R² is chlorine. 5.A compound according to claim 1 wherein R³ is a group of formula II. 6.A compound according to claim 1 wherein R³ is a group of formula IIIwherein n is
 2. 7. A compound according to claim 6 wherein R⁵ ishydrogen.
 8. A compound according to claim 1 wherein R⁴ is cyclopropyland m is
 1. 9. A compound according to claim 1 wherein R⁴ is methoxy andm is
 2. 10. A compound according to claim 1 wherein R⁴ is atetrahydrofuryl or 1,3-dioxolanyl group.
 11. A compound according toclaim 1 which isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylmethoxy-4-amino-5-chloro-benzamide.12. A compound according to claim 1 which isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-(cyclopentyloxy)-4-amino-5-chlorobenzamide.13. A pharmaceutical composition comprising, as active ingredient, acompound, salt or N-oxide according to claim 1 together with apharmaceutically acceptable diluent or carrier.
 14. A method ofcombatting gastro-intestinal disorders which comprises administering toa patient suffering from or expected to suffer from gastro-intestinaldisorders an effective amount of a compound of formula I or apharmacologically acceptable salt or N-oxide thereof as defined inclaim
 1. 15. A compound of the formula: ##STR25## wherein R¹, R², R⁴, mand n are as defined in claim 1.